Opioid receptors belong to the superfamily of G-protein coupled receptors that mediate the analgesic and other pharmacological actions of morphine and related opioid drugs. In the past, it was believed that only a single opioid binding site existed. The existence of at least three distinct subtypes of opioid receptors, designated μ, δ and κ receptors, in the central nervous system and periphery is now well established. Human μ, δ and κ receptors have been cloned and have been shown to belong to the G protein-coupled receptor (GPCR) superfamily.
The existence of three distinct opioid receptor types, μ, δ and κ, is confirmed by the recent cloning of these three opioid receptors from mouse, rat and human cDNAs. All three of the opioid receptor types are located in human brain or spinal cord tissues and each has a role in the mediation of pain. Opiates are used extensively for the treatment of pain and are the most effective analgesic agents available. Morphine and its analogues currently prescribed as potent analgesics are μ selective ligands. The general administration of these medications is limited by side-effects such as respiratory depression, depression of gastrointestinal motility and development of tolerance and physical dependence.
The development of potent and selective antagonist and agonist ligands for each of these opioid receptor subtypes has been the goal of medicinal chemists for many years because of their potential usefulness as pharmacological tools and as therapeutic agents. Among the μ, δ and κ receptors, the development of antagonist and agonist ligands acting through the δ receptor has become the focus of research in recent years due to the therapeutic potential of opioid δ ligands. Various studies suggest that δ selective agonists could be potentially useful as analgesics devoid of side effects such as respiratory depression and physical dependence side effects. Selective antagonists of δ receptors have been shown to display immunomodulatory effects as well as modulatory effects on the actions of drugs of abuse such as cocaine and methamphetamines. Moreover, recent studies using rodents have demonstrated that δ opioid antagonists are capable of preventing the development of tolerance and dependence to μ agonist such as morphine without interfering with the μ opioid antinociception.
It has been found that a number of ligands synthetically derived from naltrexone display significant selectivity toward the δ receptors. Among these, the indolomorphinan naltrindole is presently widely used as δ selective antagonist ligand, and other ligands such as its 5′-isothiocyanate derivative, benzofuran analog, and (E)-7-benzylidenenaltrexone have been useful in the pharmacological characterization of δ opioid receptor subtypes.
Continuing efforts exist for developing subtype selective nonpeptide opioid ligands.